title: Prostamide F(2) α receptor antagonism combined with inhibition of FAAH may block the pro-inflammatory mediators formed following selective FAAH inhibition.
abstract: OBJECTIVE
  Prostamides are lipid mediators formed by COX-2-catalysed oxidation of the endocannabinoid anandamide and eliciting effects often opposed to those caused by anandamide. Prostamides may be formed when hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) is physiologically, pathologically or pharmacologically decreased. Thus, therapeutic benefits of FAAH inhibitors might be attenuated by concomitant production of prostamide F2 α . This loss of benefit might be minimized by compounds designed to selectively antagonize prostamide receptors and also inhibiting FAAH.
  
  
  METHODS
  Inhibition of FAAH by a series of selective antagonists of prostamide receptors, including AGN 204396, AGN 211335 and AGN 211336, was assessed using rat, mouse and human FAAH in vitro, together with affinity for human recombinant CB1 and CB2 receptors. Effects in vivo were measured in a model of formalin-induced inflammatory pain in mice.
  
  
  RESULTS
  The prostamide F2 α receptor antagonists were active against mouse and rat FAAH in the low μM range and behaved as non-competitive and plasma membrane-permeant inhibitors. AGN 211335, the most potent inhibitor of rat FAAH (IC50  = 1.2 μM), raised exogenous anandamide levels in intact cells and also bound to cannabinoid CB1 receptors. Both AGN 211335 and AGN 211336 (0.25-1 mg·kg(-1) , i.p.) inhibited the formalin-induced nociceptive response in mice.
  
  
  CONCLUSIONS
  Synthetic compounds with indirect agonist activity at cannabinoid receptors and antagonist activity at prostamide receptors can be developed. Such compounds could be used as alternatives to selective FAAH inhibitors to prevent the possibility of prostamide F2 α -induced inflammation and pain.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Jose
authors.initials: J
authors.lastname: Martos
authors.forename: Jenny
authors.initials: J
authors.lastname: Wang
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.forename: Vittoria
authors.initials: V
authors.lastname: Palmieri
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: David
authors.initials: D
authors.lastname: Woodward
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D002415:Cats; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D011982:Receptors, Prostaglandin; D000099252:Fatty Acid Amide Hydrolases; C493494:prostaglandin F2alpha ethanolamide
keywords: FAAH; PGs; anandamide; endocannabinoid; pain; prostamides